去势抵抗是前列腺癌(PC)致死的重要原因，但机制未明。我们的前期研究证实ERG过表达与PC侵袭进展密切相关[J Mol Diagn 2010; Clin Cancer Res 2012]。进一步研究发现，去势抵抗型PC中circRNA-GLIS3表达明显高于激素依赖型PC；circGLIS3可吸附miR145，调控ERG表达，促进PC细胞去势抵抗。鉴于前期发现ERG与表观遗传调控存在密切关联，我们提出circGLIS3促进PC去势抵抗新机制：高表达circGLIS3通过发挥ceRNA活性，减弱miR145对ERG抑制，组蛋白H3K27甲基化，促进PC去势抵抗。本项目拟通过分子、体外及动物和临床标本等水平的一系列实验，力图解析以circGLIS3→ceRNA→miRNAs→ERG通路为核心的PC去势抵抗分子机制，为PC的治疗提供重要的分子干预靶点。

Castration-resistance is the primary cause of mortality from prostate cancer. However, the molecular mechanisms of castration-resistance in prostate cancer remains obscure. Our previous studies showed that ERG overexpression is critically associated with prostate cancer invasiveness and metastases [J Mol Diagn 2010; Clin Cancer Res 2012]. Our recent investigations further confirmed: (1) CircRNA-GLIS3 expression was significantly higher in patients with castration-resistant prostate cancer, compared with androgen dependent prostate cancer. (2) CircRNA-GLIS3 could function as a competing endogenous RNA to regulate ERG expression by sponging miR-145 in inducing castration-resistance in prostate cancer cells. Herein, based on these findings and the close correlation between ERG and epigenetic regulation shown by our recent publication, we speculate and present the novel mechanisms underlying circRNA-GLIS3-inducing castration-resistance in prostate cancer: circRNA-GLIS3 may act as a competing endogenous RNA, effectively becoming a sink for miR-145, thereby modulating the derepression of ERG. Subsequently, histone H3K27 methylation in its promoter is increased, thus contributes to castration-resistance in prostate cancer. Based on a series of molecular, in vitro/in vivo, and clinical sample experiments, our present study makes endeavor to elucidate the molecular mechanisms of castration-resistance in prostate cancer focusing on circGLIS3→ceRNA→miRNAs→ERG regulatory network. These results may provide novel and imperative molecular targets for the intervention of castration-resistant prostate cancer.